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After decades of its epidemic, the human immunodeficiency virus type 1 (HIV-1) is still rampant worldwide. An effective vaccine is considered to be the ultimate strategy to control and prevent the spread of HIV-1. To date, hundreds of clinical trials for HIV-1 vaccines have been tested. However, there is no HIV-1 vaccine available yet, mostly because the immune correlates of protection against HIV-1 infection are not fully understood. Currently, a variety of recombinant viruses-vectored HIV-1 vaccine candidates are extensively studied as promising strategies to elicit the appropriate immune response to control HIV-1 infection. In this review, we summarize the current findings on the immunological parameters to predict the protective efficacy of HIV-1 vaccines, and highlight the latest advances on HIV-1 vaccines based on viral vectors.

The quest for immune correlates of protection continues to slow vaccine development. To date, only vaccine-induced antibodies have been confirmed as direct immune correlates of protection against a plethora of pathogens. Vaccine immunologists, however, have learned through extensive characterizations of humoral responses that the quantitative assessment of antibody responses alone often fails to correlate with protective immunity or vaccine efficacy. Despite these limitations, the simple measurement of post-vaccination antibody titers remains the most widely used approaches for vaccine evaluation. Developing and performing functional assays to assess the biological activity of pathogen-specific responses continues to gain momentum; integrating serological assessments with functional data will ultimately result in the identification of mechanisms that contribute to protective immunity and will guide vaccine development. One of these functional readouts is phagocytosis of antigenic material tagged by immune molecules such as antibodies and/or complement components. This review summarizes our current understanding of how phagocytosis contributes to immune defense against pathogens, the pathways involved, and defense mechanisms that pathogens have evolved to deal with the threat of phagocytic removal and destruction of pathogens.

Congenital cytomegalovirus (cCMV) might occur as a result of the human cytomegalovirus (HCMV) primary (PI) or nonprimary infection (NPI) in pregnant women. Immune correlates of protection against cCMV have been partly identified only for PI. Following either PI or NPI, HCMV strains undergo latency. From a diagnostic standpoint, while the serological criteria for the diagnosis of PI are well-established, those for the diagnosis of NPI are still incomplete. Thus far, a recombinant gB subunit vaccine has provided the best results in terms of partial protection. This partial efficacy was hypothetically attributed to the post-fusion instead of the pre-fusion conformation of the gB present in the vaccine. Future efforts should be addressed to verify whether a new recombinant gB pre-fusion vaccine would provide better results in terms of prevention of both PI and NPI. It is still a matter of debate whether human hyperimmune globulin are able to protect from HCMV vertical transmission. In conclusion, the development of an HCMV vaccine that would prevent a significant portion of PI would be a major step forward in the development of a vaccine for both PI and NPI.

BACKGROUND: HIV-1 CRF01_AE is dominant in Thailand where RV144 vaccine trial was conducted. To study immune correlates of protection in ongoing trials, CRF01_AE derived reagents are essential. Here we present a panel of 14 HIV-1 infectious molecular clones (IMC) identified from different stages of infection, and characterization of their neutralization sensitivity using two standard assays. METHODS: One full-length IMC was constructed using a transmitted-founder virus to express Renilla luciferase (LucR) reporter gene and full-length envelopes (envs) of exogenous HIV-1. A panel of IMCs was generated, expressing envs of viruses from acute (Fiebig stages I/II and I-IV) and chronic (>Febig VI) infection. Neutralization assays were performed using TZM-bl or A3R5 cell lines, and sera or monoclonal antibodies (mAbs). Wilcoxon matched-paired test was used to assess neutralization differences between assays and reagents; correlation coefficients were evaluated by linear regression. RESULTS: Neutralization potency observed was significantly higher in the A3R5 assay when testing mAbs and serum pools (p

Robust and well-established immunological assays and firm immune correlates of protection that can predict disease outcome and/or vaccine efficacy are essential to adequately assess human immune responses to infection and vaccination. The availability of reagents and calibrated controls is also critically important to standardize assays and generate comparable results among different laboratories. The workshop "Human Immune Responses against Shigella and ETEC: Current Advances and the Path Forward" held during the VASE meeting provided an opportunity to disseminate and discuss recent advances in the field of Shigella and ETEC immunology, identify research needs, and propose collaborative activities to advance the field. Four presentations featured current knowledge on humoral and cellular immune responses to Shigella and ETEC during infection and vaccination. A discussion followed on immunological methods relevant for clinical studies, immune parameters associated with protection, harmonization of assays among laboratories, and availability of reagents and standards. Specific recommendations proposed to facilitate "the path forward" included supporting communication among scientists, harmonization of assays and sharing of protocols, the creation of a repository of reagents and calibrated controls and distribution of such material to the research community, and expansion of exploratory studies to better understand the interactions between these pathogens and the human immune system and the ensuing responses.

Hantaviruses (HVs) are rodent-transmitted viruses that can cause hantavirus cardiopulmonary syndrome (HCPS) in the Americas and hemorrhagic fever with renal syndrome (HFRS) in Eurasia. Together, these viruses have annually caused approximately 200,000 human infections worldwide in recent years, with a case fatality rate of 5–15% for HFRS and up to 40% for HCPS. There is currently no effective treatment available for either HFRS or HCPS. Only whole virus inactivated vaccines against HTNV or SEOV are licensed for use in the Republic of Korea and China, but the protective efficacies of these vaccines are uncertain. To a large extent, the immune correlates of protection against hantavirus are not known. In this review, we summarized the epidemiology, virology, and pathogenesis of four HFRS-causing viruses, HTNV, SEOV, PUUV, and DOBV, and two HCPS-causing viruses, ANDV and SNV, and then discussed the existing knowledge on vaccines and therapeutics against these diseases. We think that this information will shed light on the rational development of new vaccines and treatments.

Tuberculosis (TB) is one of the major global health concerns. There has been a lack of an effective vaccine strategy. The Bacillus Calmette-Guerin (BCG), the only licensed vaccine against TB, is not effective against adult pulmonary TB, the highly contagious form of TB. In the past two decades or so, many novel TB vaccines have been developed, and some of them were evaluated in clinical trials. However, the lack of validated immune correlates to assess the clinical relevance of novel TB vaccines before their entry into costly efficacy trials is a huge challenge to the field of TB vaccine development. Here we describe a general protocol for the procedure of a systematic immunological approach that can be utilized to better assess the clinical relevance of TB vaccine-activated T cells in early phases of clinical studies.

A correlate of protection is an immunological assay that predicts protection against infection. In clinical vaccine trials, correlates of protection are widely used as surrogate endpoints for vaccine efficacy. The function specifying the relationship between immunogenicity values and the probability of protection against infection is called the protection curve. It is demonstrated how the parameters of the protection curve can be estimated from both challenge study data and vaccine efficacy data. Also explained is how a threshold of protection can be estimated from the protection curve. The generalizable of estimated protection curves is discussed.

Introduction: It's been 20 years since the first report of a recombinant vaccine that protected against leptospirosis. Since then, numerous recombinant vaccines have been evaluated; however, no recombinant vaccine candidate has advanced to clinical trials. With the ever-increasing burden of leptospirosis, there is an urgent need for a universal vaccine against leptospirosis.Areas covered: This review covers the most promising vaccine candidates that induced significant, reproducible, protection and how advances in the field of bioinformatics has led to the discovery of hundreds of novel protein targets. The authors also discuss the most recent findings regarding the innate immune response and host-pathogen interactions and their impact on the discovery of novel vaccine candidates. In addition, the authors have identified what they believe are the most challenging problems for the discovery and development of a universal vaccine and their potential solutions.Expert opinion: A universal vaccine for leptospirosis will likely only be achieved using a recombinant vaccine as the bacterins are of limited use due to the lack of a cross-protective immune response. Although there are hundreds of novel targets, due to the lack of immune correlates and the need for more research into the basic microbiology of Leptospira spp., a universal vaccine is 10-15 years away.

Among immune correlates of clinical responses, tumor-specific neoantigens took the spotlight as relevant targets for cancer immunotherapy. The implementation of pipelines for personalized cancer therapy remains challenging due to the privacy, that is patient-specificity, of neoantigens and the low-frequency of neoantigen-specific T cells in blood and tumor samples. To overcome these obstacles, recent developments in the field of biotechnology have allowed the multiplexed identification of neoepitope-specific T cells. This review addresses the pros and cons of conventional neoantigen screening methodologies and highlights the current as well as the prospective biotechnological opportunities in the field.

Purpose The field of HIV-1 vaccinology has evolved during the last 30 years from the first viral vector HIV gene insert constructs to vaccination regimens using a myriad of strategies. These strategies now include germline-targeting, lineage-based, and structure-guided immunogen design. This narrative review outlines the historical context of HIV vaccinology and subsequently highlights the scientific discoveries during the last 6 years that promise to propel the field forward. Methods We conducted a search of 2 electronic databases, PubMed and EMBASE, for experimental studies that involved new HIV immunogen designs between 2013 and 2019. During the title and abstract reviews, publications were excluded if they were written in language other than English and/or were a letter to the editor, a commentary, or a conference-only presentation. We then used ClinicalTrials.gov to identify completed and ongoing clinical trials using these strategies. Findings The HIV vaccinology field has undergone periods of significant growth during the last 3 decades. Findings elucidated in preclinical studies have revealed the importance of the interaction between the cellular and humoral immune system. As a result, several new rationally designed vaccine strategies have been developed and explored in the last 6 years, including native-like envelope trimers, nanoparticle, and mRNA vaccine design strategies among others. Several of these strategies have shown enough promise in animal models to progress toward first-in-human Phase I clinical trials. Implications Rapid developments in preclinical and early-phase clinical studies suggest that a tolerable and effective HIV vaccine may be on the horizon.

The RV144 vaccine trial is the only clinical study to have shown a modest but statistically significant decrease in HIV infection risk. RV144 and the subsequent studies identifying the level of V1V2-specific antibodies as a correlate of reduced infection risk are still controversial despite many papers supporting and expanding the initial study. We address these controversies and summarize active-immunization and passive-immunization experiments in nonhuman primates that support the initial finding.

Herpes zoster (HZ) has high morbidity in people living with HIV (PLHIV). We investigated immunological factors that correlated with the development of HZ in PLHIV with controlled HIV replication on antiretroviral therapy (ART). PLHIV who developed HZ on ART (cases), with undetectable plasma HIV RNA, and CD4 counts ≥200 cells/μL were matched 1:1 to controls by CD4 count, age, gender, race, and duration of ART. Varicella-zoster virus (VZV)-specific T cells and circulating regulatory T cells (Treg) were measured by flow cytometry before and after HZ. Differences between cases and controls were assessed by paired t-tests and longitudinal changes by Wilcoxon signed rank test. HZ cases (N = 31) had higher CD4(+)FOXP3(+)CD25(+)% Treg before HZ compared with 31 controls. After VZV ex vivo restimulation, cases had lower T cell responses, including CD8(+)perforin(+)% cytotoxic T lymphocytes (CTLs), CD4(+)IL10(+)%, and CD4(+)TGFβ(+)% compared with controls. Overall, Treg negatively correlated with VZV-specific Th1 responses. Moreover, Treg decreased over time on ART in HZ cases, VZV-CTLs were stable and did not increase even after HZ. Increased circulating Treg and decreased VZV-specific T cell immune responses were associated with the risk of HZ in PLHIV. The kinetics of Treg over time, but not of VZV-CTLs, paralleled the natural history of HZ, whose incidence decreases over time on effective ART.

Background Rift Valley fever virus (RVFV) is a zoonotic arbovirus endemic to large areas of Africa and the Arabian peninsula that causes a significant annual burden of disease in ruminant animals, and is associated with periodic outbreaks in human populations. RVFV causes a wide spectrum of disease in infected patients ranging from a self-limiting febrile illness to hepatitis, encephalitis, hemorrhagic fever, and death. Despite the significant economic and public health impact of RVFV, there are no currently available vaccines or therapeutics available for RVFV. Methods Previous work has established that vaccination with an attenuated strain of RVFV, RVFV-ΔNSs, confers protection against subsequent lethal challenge in a murine model of infection. To characterize mechanistic immune correlates of protection, we vaccinated C57BL/6 mice with RVFV-ΔNSs then depleted vaccinated mice of various memory lymphocyte subsets, including CD4+, CD8+, CD4+/CD8+ T-cells before challenging mice with a lethal dose of WT RVFV. To assess for the role of antibodies in providing protection, we depleted mice of their B cells prior to vaccination with RVFV-ΔNSs, confirmed the lack of RVFV specific antibodies, and then challenged them with lethal WT RVFV. To determine the minimal immunologic factors required for protection, we vaccinated a series of donor mice, transferred either immunoglobulins or splenocytes to naïve recipient mice, then challenged them with WT RVFV. Results Vaccination with RVFV-ΔNSs protected mice from subsequent challenge, and this protection was not abrogated by depletion of CD4+, CD8+, or combined CD4+ and CD8+ lymphocytes, suggesting that RVFV-specific T-cells are dispensable for protection in the presence of virus specific antibodies. Vaccinated mice depleted of CD20+ B-cells were also protected against WT challenge, suggesting that B-cells/antibodies are also dispensable for protection in the presence of an intact T-cell response. Passive transfer of antibodies from vaccinated mice to recipient mice protected them against subsequent WT challenge, demonstrating that antibodies are sufficient for protection. Adoptive transfer of total splenocytes protected mice against subsequent WT challenge, indicating that lymphocytes are also sufficient to mediate protection. Conclusions In this study we defined the mechanistic immune correlates of protection following vaccination with attenuated RVFV-ΔNSs against WT RVFV in a murine model. Here, we have shown that both humoral and cellular immunity are sufficient to mediate protection in recipient animals, and can compensate for each other when one is missing. These results further our understanding of the protective immunologic response to infection by RVFV, and will help inform further vaccine development efforts against this important emerging pathogen.

e18043 Background: We aim to evaluate the efficacy and safety for single dose of preoperative D with or without T in patients with operable HNSCC with immune correlates. Methods: Patients with histologically confirmed, potentially resectable, stage II, III, and IVA HNSCC were eligible. Enrolled patients were randomized into D or D+T, stratified by primary site and human papilloma (HPV) infection status assessed by p16 expression. A single dose of preoperative D (1500mg) or D+T (1500mg+75mg) was administered and followed 2 to 8 weeks later by surgical tumor resection with curative intent. Postoperative (chemo) radiation (PO-CRT) was planned based on standard guidelines, followed by maintenance with D every 4 weeks for one year. Pathology response was quantified as the proportion of the resection bed with viable tumor, tumor necrosis, fibrosis, and inflammation. The primary objective was to determine the local recurrence rate. Secondary endpoints included pathologic response, safety and tolerability, disease-free survival, and immune dynamics incorporating multiple immunofluorescence and single cell transcriptomic analysis. A total 48 patients are planned to be enrolled. Results: As of Jan. 31, 2021, a total 36 patients were enrolled and received surgical resections with available data for pathologic response (D: 16 patients, D+T: 20 patients). Patient characteristics of both arms were well-balanced: hypopharynx/larynx/oral cavity as primary site (12.5%/12.5%/18.8%/56.3% in D, 20.0%/10.0%/10.0%/60.0% in D+T); HPV positivity (50.0% in D, 50.0% in D+T); cT1/T2/T3/T4 (6.3%/37.5%/31.3%/25.0% in D, 10.0%/25.0%/40.0%/25.0% in D+T); cN0/N1/N2/N3 (25.0%/18.8%/50.0%/6.3% in D, 30.0%/30.0%/40.0%/0% in D+T). Significant tumor shrinkage defined as more than 30% of size reduction was observed in 43.7% (7/16), including 2 patients with complete response in D and 20.0% (4/20) in D+T. During 128 days of median follow-ups, local recurrence was observed in 2 patients of D+T arm (5.6%). HPV positivity was numerically associated with favorable treatment response (average tumor shrinkage; -21.8% in p16-positive vs. -6.4% in p16-negative). Meaningful pathologic response was achieved in terms of tumor necrosis (average 10.3% in D, 5.5% in D+T), fibrosis (average 13.4% in D, 10.3% in D+T), and inflammation (average 15.0% in D, 5.8% in D+T), without significant differences according to HPV positivity. After preoperative D or D+T, serious adverse events and unexpected surgical complications did not occur. Conclusions: These early data suggested that preoperative D or D+T in patients with operable HNSCC was safe and feasible and had the potential to provide clinical benefits. The trial is ongoing and the updated outcomes with immune correlates including immunofluorescence and single cell transcriptomic analysis will be presented. Clinical trial information: NCT03737968.

Development of an efficacious HIV-1 vaccine is a major priority for improving human health worldwide. Vaccine-mediated protection against human pathogens can be achieved through elicitation of protective innate, humoral, and cellular responses. Identification of specific immune responses responsible for pathogen protection enables vaccine development and provides insights into host defenses against pathogens and the immunological mechanisms that most effectively fight infection. Defining immunological correlates of transmission risk in preclinical and clinical HIV-1 vaccine trials has moved the HIV-1 vaccine development field forward and directed new candidate vaccine development. Immune correlate studies are providing novel hypotheses about immunological mechanisms that may be responsible for preventing HIV-1 acquisition. Recent results from HIV-1 immune correlates work has demonstrated that there are multiple types of immune responses that together, comprise an immune correlate-thus implicating polyfunctional immune control of HIV-1 transmission. An in depth understanding of these complex immunological mechanisms of protection against HIV-1 will accelerate the development of an efficacious HIV-1 vaccine.

Roles of human IL-37 in infections remain poorly characterized. Although plasma IL-37 is elevated in patients with tuberculosis (TB), IL-37 source and immune correlate in TB have not been investigated. It is also unknown whether and how TB can influence the ability of immune cells to mount innate responses of IL-37 and pre-inflammatory cytokines. Here, we demonstrated that IL-37b-producing monocytes coincided with a source of elevated plasma IL-37b in TB patients. While IL-37b production in TB was associated with prolonged/complicated TB, TB burdens and inflammatory reactions, it negatively correlated with immune responses of pro-inflammatory cytokines IL-1β, IL-6 and TNF-α or IL-10. Interestingly, mycobacterial re-infection of monocytes from TB patients, but not healthy BCG-vaccinated controls, enhanced or sustained IL-37b production by cultured monocytes. TB-sensitized monocytes from TB patients mounted more robust immune responses of IL-37b than those of pre-inflammatory cytokines during mycobacterial re-infection in culture. Our data represent new findings in terms of IL-37b responses, immune correlates and potential mechanisms in TB patients.

The immune correlate of host resistance induced by reinfection of Trichinella spiralis remains unclear. In this study, we investigated immune correlates between the resistance and serum IgG antibody level, CD23+ IgM+ B cells, and eosinophil responses induced by T. spiralis reinfection. Mice were primarily infected with 10 or 100 T. spiralis larvae (10 TS, 100 TS), respectively, and after 4 weeks, they were challenge infected with 100 T. spiralis larvae (10-100 TS, 100-100 TS). Upon challenge infections, 10-100 TS mice induced significantly higher levels of T. spiralis-specific total IgG antibody responses in sera and antibody secreting cell responses in spleens compared to 100-100 TS mice, resulting in significantly reduced worm burdens in 10-100 TS mice (60% and 70% reductions for adult and larvae, respectively). Higher levels of eosinophils were found in mice primarily infected with 10 TS compared to those of 100 TS at week 8 upon challenge. CD23+ IgM+ B cells were found to be increased significantly in mice primarily infected with 10 TS. These results indicate that primary infection of 10 larvae of T. spiralis, rather than 100 larvae, induces significant resistance against reinfection which closely correlated with T. spiralis-specific IgG, eosinophil, and CD23+ IgM+ B cell responses.

Summary The 4th Global Forum on TB Vaccines, convened in Shanghai, China, from 21 – 24 April 2015, brought together a wide and diverse community involved in tuberculosis vaccine research and development to discuss the current status of, and future directions for this critical effort. This paper summarizes the sessions on Immunopathogenesis of Tuberculosis, and Immunopathogenesis and Novel Mechanisms of Vaccine Activity. Summaries of all sessions from the 4th Global Forum are compiled in a special supplement of Tuberculosis .

Chagas disease is a major neglected tropical disease, transmitted predominantly by triatomine insect vectors, but also through congenital and oral routes. While endemic in the Americas, it has turned into a global disease. Because of the current drug treatment limitations, a vaccine would represent a major advancement for better control of the disease. Here, we review some of the rationale, advances, and challenges for the ongoing development of a vaccine against Chagas disease. Recent pre-clinical studies in murine models have further expanded (i) the range of vaccine platforms and formulations tested; (ii) our understanding of the immune correlates for protection; and (iii) the extent of vaccine effects on cardiac function, beyond survival and parasite burden. We further discuss outstanding issues and opportunities to move Chagas disease development forward in the near future.

Profiling of serological responses to establish the landscape of antibody specificities in individuals exposed to pathogens or vaccines is crucial for (a) revealing humoral immune correlates of protection; (b) uncovering markers of pathogen exposure; and (c) identifying antigens and epitopes associated with disease vs. protection. Establishing the antigenic profile of serological responses requires either expensive microarrays or labor- and time-intensive ELISA assays. Multiplex assay platforms are increasingly being evaluated for their usefulness for high-throughput testing of sera or plasma. The methodology described here utilizes a plate-based assay that allows the simultaneous detection of up to ten antigens per well in a 96 well format using an electrochemiluminescence immunoassay (ECLIA).•The newly developed protocol outlines high-throughput profiling of serological responses using a multiplex testing platform with subsequent computational analysis.•The protocol is a modification of the basic assay development manual from the manufacturer of the MESO QuickPlex SQ 120 instrument (MSD, Gaithersburg, MD) and can be used for synthetic peptides as well as full length proteins.•The protocol can be applied to map serological responses to pathogens or pathogen-derived antigens to establish serological profiles in search for biomarkers or immune correlates., Graphical abstract Image, graphical abstract

Mycobacterium tuberculosis (Mtb) continues to be a global scourge with 10.4 million cases of TB and 1.7 million deaths each year. The burgeoning molecular biology is both clarifying Mtb-induced pathology, but also raising new questions with many major challenges remaining: Immune correlates of protection are still to be clarified. Clinical biomarkers that predict disease progression are needed. Non-sputum quantitative means to monitor treatment efficacy are needed. Herein, we briefly review the spectrum of Mtb infection and pathology and then discuss how novel studies in immunology, transcriptomics and epigenomics could be translated into clinical care.

Bordetella pertussis is the causative agent of whooping cough, commonly referred to as pertussis. Although the incidence of pertussis was reduced through vaccination, during the last thirty years it has returned to high levels in a number of countries. This resurgence has been linked to the switch from the use of whole-cell to acellular vaccines. Protection afforded by acellular vaccines appears to be short-lived compared to that afforded by whole cell vaccines. In order to inform future vaccine improvement by identifying immune correlates of protection, a human challenge model of B. pertussis colonisation has been developed. Accurate measurement of colonisation status in this model has required development of a qPCR-based assay to enumerate B. pertussis in samples that distinguishes between viable and dead bacteria. Here we report the development of this assay and its performance in the quantification of B. pertussis from human challenge model samples. This assay has future utility in diagnostic labs and in research where a quantitative measure of both B. pertussis number and viability is required.

The quest for a licensed effective vaccine against malaria remains a global priority. Even though classical vaccine design strategies have been successful for some viral and bacterial pathogens, little success has been achieved for Plasmodium falciparum, which causes the deadliest form of malaria due to its diversity and ability to evade host immune responses. Nevertheless, recent advances in vaccinology through high throughput discovery of immune correlates of protection, lymphocyte repertoire sequencing and structural design of immunogens, provide a comprehensive approach to identifying and designing a highly efficacious vaccine for malaria. In this review, we discuss novel vaccine approaches that can be employed in malaria vaccine design.

Influenza viruses circulate worldwide causing annual epidemics that have a substantial impact on public health. This is despite vaccines being in use for over 70 years and currently being administered to around 500 million people each year. Improvements in vaccine design are needed to increase the strength, breadth, and duration of immunity against diverse strains that circulate during regular epidemics, occasional pandemics, and from animal reservoirs. Universal vaccine strategies that target more conserved regions of the virus, such as the hemagglutinin (HA)-stalk, or recruit other cellular responses, such as T cells and NK cells, have the potential to provide broader immunity. Many pre-pandemic vaccines in clinical development do not utilize new vaccine platforms but use “tried and true” recombinant HA protein or inactivated virus strategies despite substantial leaps in fundamental research on universal vaccines. Significant hurdles exist for universal vaccine development from bench to bedside, so that promising preclinical data is not yet translating to human clinical trials. Few studies have assessed immune correlates derived from asymptomatic influenza virus infections, due to the scale of a study required to identity these cases. The realization and implementation of a universal influenza vaccine requires identification and standardization of set points of protective immune correlates, and consideration of dosage schedule to maximize vaccine uptake.

The Bacille Calmette Guerin (BCG) vaccine can provide decades of protection against tuberculosis (TB) disease, and although imperfect, BCG is proof that vaccine mediated protection against TB is a possibility. A new TB vaccine is, therefore, an inevitability; the question is how long will it take us to get there? We have made substantial progress in the development of vaccine platforms, in the identification of antigens and of immune correlates of risk of TB disease. We have also standardized animal models to enable head-to-head comparison and selection of candidate TB vaccines for further development. To extend our understanding of the safety and immunogenicity of TB vaccines we have performed experimental medicine studies to explore route of administration and have begun to develop controlled human infection models. Driven by a desire to reduce the length and cost of human efficacy trials we have applied novel approaches to later stage clinical development, exploring alternative clinical endpoints to prevention of disease outcomes. Here, global leaders in TB vaccine development discuss the progress made and the challenges that remain. What emerges is that, despite scientific progress, few vaccine candidates have entered clinical trials in the last 5 years and few vaccines in clinical trials have progressed to efficacy trials. Crucially, we have undervalued the knowledge gained from our “failed” trials and fostered a culture of risk aversion that has limited new funding for clinical TB vaccine development. The unintended consequence of this abundance of caution is lack of diversity of new TB vaccine candidates and stagnation of the clinical pipeline. We have a variety of new vaccine platform technologies, mycobacterial antigens and animal and human models. However, we will not encourage progression of vaccine candidates into clinical trials unless we evaluate and embrace risk in pursuit of vaccine development.

Background Despite improvements in treatments, the 5-year survival of GEA patients (pts) is disappointing. Individual molecular subtypes display preferential responses to PD-1 blockade. M, an investigational Fc-optimized anti-HER2 monoclonal antibody, is being tested in combination with P in HER2+ GEA post trastuzumab. We present gene expression data from archival FFPE biopsies. Methods 55 pt samples were assessed by NanoString PanCancer IO360™ assay. Immune signature scores are presented as fold changes (FC) and analyzed by unpaired t-test. Associations examined include baseline IHC PD-L1 (pos vs neg) and HER2 expression (IHC3+ vs 2+), ERBB2 mRNA, inflamed tumor microenvironment (TME), radiographic response, and GC vs GEJ. Results ERBB2 mRNA was increased in pts with HER2 IHC3+ vs 2 + (5.6 FC, p Conclusions Our study documents for the first time ERBB2 expression and inflamed TME in GEA, which can help differentiate immunologically between GC and GEJ tumors. Clinical trial identification NCT02689284. Legal entity responsible for the study MacroGenics, Inc. Funding MacroGenics, Inc. Disclosure S. Rutella: Leadership role: Society for Immunotherapy of Cancer; Research grant / Funding (institution): John and Lucille van Geest Foundation. S.E. Church: Shareholder / Stockholder / Stock options, Full / Part-time employment: NanoString Technologies. A.H. Sullivan: Shareholder / Stockholder / Stock options, Full / Part-time employment: NanoString Technologies. S. Warren: Shareholder / Stockholder / Stock options, Full / Part-time employment: NanoString Technologies. J. Baughman: Shareholder / Stockholder / Stock options, Full / Part-time employment: MacroGenics, Inc. J. Muth: Shareholder / Stockholder / Stock options, Full / Part-time employment: MacroGenics, Inc. H. Park: Research grant / Funding (institution): Amgen; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): BeiGene; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Gilead Sciences; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Macrogenics; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Millennium; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Puma Biotechnology; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Vertex. H. Uronis: Shareholder / Stockholder / Stock options, Full / Part-time employment: GeneCentric; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Research grant / Funding (institution): Advaxis; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Lycera; Research grant / Funding (institution): Macrogenics. Y. Kang: Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self): DAE HWA Pharmaceutical; Advisory / Consultancy: Lilly/ImClone; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Ono Pharmaceutical; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Taiho Pharmaceutical; Research grant / Funding (self): LSK Biopharma. M.C.H. Ng: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD Oncology; Honoraria (self), Travel / Accommodation / Expenses: Taiho Pharmaceutical; Advisory / Consultancy: Bristol-Myers Squibb; Research grant / Funding (institution): ASLAN Pharmaceuticals. P. Enzinger: Advisory / Consultancy: Astellas Pharma; Advisory / Consultancy: Five Prime Therapeutics; Advisory / Consultancy: Merck; Advisory / Consultancy: Taiho Pharmaceutical. K.W. Lee: Research grant / Funding (institution): Array BioPharma; Research grant / Funding (institution): ASLAN Pharmaceuticals; Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): Green Cross Corp; Research grant / Funding (institution): LSK BioPharma; Research grant / Funding (institution): Macrogenics; Research grant / Funding (institution): Merck KGaA; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Pharmacyclics. K. Huber: Full / Part-time employment: Macrogenics, Inc. A. Wynter-Horton: Shareholder / Stockholder / Stock options, Full / Part-time employment: MacroGenics, Inc. D. Li: Shareholder / Stockholder / Stock options, Full / Part-time employment: MacroGenics, Inc. Y. Bang: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca/MedImmune; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): BeiGene; Advisory / Consultancy, Research grant / Funding (institution): Green Cross; Advisory / Consultancy: Hanmi; Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Advisory / Consultancy, Research grant / Funding (institution): MSD Oncology; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Samyang; Advisory / Consultancy, Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): CKD; Research grant / Funding (institution): Curis; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Macrogenics; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Takeda. J. Davidson-Moncada: Shareholder / Stockholder / Stock options, Full / Part-time employment: MacroGenics, Inc. D.V. Catenacci: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self): Five Prime Therapeutics; Honoraria (self), Speaker Bureau / Expert testimony: Foundation Medicine; Honoraria (self), Advisory / Consultancy: Genentech/Roche; Honoraria (self): Genmab; Honoraria (self): Gritstone Oncology; Honoraria (self), Speaker Bureau / Expert testimony: Guardant Health; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self): NantOmics; Honoraria (self): OncoPlex Diagnostics; Honoraria (self), Advisory / Consultancy: Taiho Pharmaceuticsal; Advisory / Consultancy: Astellas Pharma. All other authors have declared no conflicts of interest.

An international workshop to discuss the role of Human Challenge Trials (HCT) in vaccine development was held in Strasbourg, France from 29 September to 1 October 2015. In addition to scientific presentations, several panel discussions focused on key questions and proposed recommendations, including the acknowledgement that HCT have proven to be useful tools to explore vaccine targets, identify immune correlates of protection, and evaluate clinical efficacy, and when appropriate they should be continued and encouraged. In some cases, a HCT may be the only feasible way to move forward with development of an investigational product. HCT must be strongly scientifically justified, because the need for a given investigational objective must be always balanced against the risks a HCT may pose, understanding that an infectious organism will be given to the study participants. It should be noted that numerous HCT have been successfully performed, safely and ethically, to the benefit of vaccine development and public health. This workshop report highlights the scientific presentations, discussions by the panelists and attendees, and twenty recommendations that emerged as considerations for future development of international guidance on the role of HCT in vaccine development and licensure.

Background Recovery after surgery is highly variable. Risk-stratifying patients based on their predicted recovery profile will afford individualized perioperative management strategies. Recently, application of mass cytometry in patients undergoing hip arthroplasty revealed strong immune correlates of surgical recovery in blood samples collected shortly after surgery. However, the ability to interrogate a patient’s immune state before surgery and predict recovery is highly desirable in perioperative medicine. Methods To evaluate a patient’s presurgical immune state, cell-type–specific intracellular signaling responses to ex vivo ligands (lipopolysaccharide, interleukin [IL]-6, IL-10, and IL-2/granulocyte macrophage colony-stimulating factor) were quantified by mass cytometry in presurgical blood samples. Selected ligands modulate signaling processes perturbed by surgery. Twenty-three cell surface and 11 intracellular markers were used for the phenotypic and functional characterization of major immune cell subsets. Evoked immune responses were regressed against patient-centered outcomes, contributing to protracted recovery including functional impairment, postoperative pain, and fatigue. Results Evoked signaling responses varied significantly and defined patient-specific presurgical immune states. Eighteen signaling responses correlated significantly with surgical recovery parameters (|R| = 0.37 to 0.70; false discovery rate < 0.01). Signaling responses downstream of the toll-like receptor 4 in cluster of differentiation (CD) 14+ monocytes were particularly strong correlates, accounting for 50% of observed variance. Immune correlates identified in presurgical blood samples mirrored correlates identified in postsurgical blood samples. Conclusions Convergent findings in pre- and postsurgical analyses provide validation of reported immune correlates and suggest a critical role of the toll-like receptor 4 signaling pathway in monocytes for the clinical recovery process. The comprehensive assessment of patients’ preoperative immune state is promising for predicting important recovery parameters and may lead to clinical tests using standard flow cytometry.

Despite 70 years of research that has intensified in the past decade, a safe and efficacious dengue vaccine has yet to be available. In addition to the expected challenges such as identifying immune correlates of protection, the dengue vaccine field has faced additional hurdles including the necessity to design a tetravalent formulation and the risk of antibody-mediated disease enhancement. Nevertheless, tetravalent live attenuated vaccine candidates have reached efficacy trials and demonstrated some benefit, despite imbalanced immunogenicity and incomplete protection against the four serotypes. Meanwhile, the development of sub-unit dengue vaccines has gained momentum. As the target of most of the neutralizing antibodies so far reported, the virus envelope E protein has been the focus of much effort and represents the leading dengue sub-unit vaccine candidate. However, its notorious poor immunogenicity has prompted the development of innovative approaches to make E-derived constructs part of the second generation dengue vaccines portfolio.

Since the identification of the Human Immunodeficiency Virus type 1 (HIV-1) as the etiologic agent of AIDS (Acquired Immunodeficiency Syndrome), many efforts have been made to stop the AIDS pandemic. A major success of medical research has been the development of the highly active antiretroviral therapy and its availability to an increasing number of people worldwide, with a considerable effect on survival. However, a safe and effective vaccine able to prevent and eradicate the HIV pandemic is still lacking. Clinical trials and preclinical proof-of-concept studies in nonhuman primate (NHP) models have provided insights into potential correlates of protection against the HIV-1 infection, which include broadly neutralizing antibodies (bnAbs), non-neutralizing antibodies targeting the variable loops 1 and 2 (V1V2) regions of the HIV-1 envelope (Env), polyfunctional antibody, and Env-specific T-cell responses. In this review, we provide a brief overview of different HIV-1 vaccine approaches and discuss the current understanding of the cellular and humoral correlates of HIV-1 immunity.

Background: Various Zika virus (ZIKV) vaccine candidates are currently in development. Nevertheless, unique challenges in clinical development and regulatory pathways may hinder the licensure of high-quality, safe, and effective ZIKV vaccines. Discussion: Implementing phase 3 efficacy trials will be difficult given the challenges of the spatio-temporal heterogeneity of ZIKV transmission, the unpredictability of ZIKV epidemics, the broad spectrum of clinical manifestations making a single definite endpoint difficult, a lack of sensitive and specific diagnostic assays, and the need for inclusion of vulnerable target populations. In addition to a vaccine, drugs for primary prophylaxis, post-exposure prophylaxis, or treatment should also be developed to prevent or mitigate the severity of congenital Zika syndrome. Conclusion: Establishing the feasibility of immune correlates and/or surrogates are a priority. Given the challenges in conducting phase 3 trials at a time of waning incidence, human challenge trials should be considered to evaluate efficacy. Continued financial support and engagement of industry partners will be essential to the successful development, licensure, and accessibility of Zika vaccines or therapeutics.